The overarching goal of this application is to identify human placental innate immune pathways and factors that alter maternal-fetal sensitivity to teratogenic virus infections. The hematogenous spread of viruses from the maternal circulation to the fetus can induce devastating consequences in the developing embryo, compromise maternal health, and jeopardize pregnancy outcome. The placenta is a primary immunological and physical barrier to the spread of viruses from both the maternal circulation and the vaginal and cervical mucosa. However, despite the importance of this barrier, relatively little is known regarding the innate immune pathways by which the placenta senses and responds to viral infections. The proposed research by the Coyne and Diamond laboratories combines expertise in virology, immunology, and placental biology to identify placental-derived innate immune pathways that bolster antiviral defenses in a placental cell-type specific manner. We have previously identified pathways employed by placental trophoblasts to restrict viral infections. These include the constitutive release of antiviral type III interferons (IFNs), which protect both maternal- and fetal- derived cells from viral infections. These previous studies suggest that trophoblasts form an innate IFN-mediated barrier to the vertical transmission of viruses and that viruses associated with fetal disease must bypass these trophoblast intrinsic pathways to be trans-placentally transmitted. In this application, we will define the innate immune antiviral pathways by which fetal-derived components of the placenta, including chorionic villi and the amnion and chorion, sense and respond to infection by known teratogenic viruses, including Zika virus (ZIKV), Rubella virus (RuV), and herpesvirus-2 (HSV-2). These studies will utilize the individual and complementary expertise of the Coyne and Diamond laboratories, who specialize in virology (CC and MD), immunology (CC and MD), placental biology (CC), and in vivo modeling of maternal-fetal transmission (MD). In addition, we will define the mechanism(s) by which disparate IFN types (type I and III) impact placental antiviral signaling and placental damage. In deciphering the underlying mechanisms that constitute placental-derived antiviral innate immune pathways, we may illuminate the basis of placental sensitivity or resistance to viruses and identify cell populations that may be particularly sensitive to viral infections during pregnancy. These studies could inform the development of innovative therapeutics designed to mitigate and/or prevent viral infections or inflammation-induced injury, thus reducing the burden of infection related feto-maternal morbidity and mortality.